During breast MRI screening a contrast agent is administered to aid in the visualization of tumors, which enhances (becomes brighter). Normal breast tissue also enhances on MRI (termed background parenchymal enhancement [BPE]) and we have shown that the degree to which this normal tissue enhances is strongly associated with breast cancer risk. It is not clear why this would be the case and the biological underpinnings of what this enhancement represents are not known. The objective of the current study is to determine the relationship between known breast cancer risk factors and BPE and to develop and validate a computer-assisted quantitative approach to the measurement of BPE. It is hypothesized that BPE may represent the breast tissue response to the hormonal profile of a woman, making it a good indicator of breast cancer risk. This will be the largest study of BPE measurements in any group of women to date and the first to address the need for a quantitative method of measurement. Three specific aims will be addressed to test our primary hypothesis and to address the overall objective of this application: 1) Develop and validate an objective quantitative measure of BPE using software for analyzing breast MRIs available at Memorial Sloan-Kettering Cancer Center (MSKCC), 2) Explore the relationship between BPE on MRI and known breast cancer risk factors in healthy high-risk pre- and post-menopausal women and 3) Determine the relationship between serum hormone levels at the time of MRI and degree of BPE in healthy high-risk postmenopausal women. The results of this study will provide crucial information regarding the relationship between BPE, a new highly predictive indicator of breast cancer risk, and known breast cancer risk factors including circulating levels of hormones. Additionally, the quantitative method developed here will yield a continuous measure of BPE, one that is expected to provide a more accurate picture of the relationship between BPE and breast cancer risk than the four-point categorical scale used by radiologists. This will allow for better classification of already high-risk women (i.e., those with a family or personal history of breast cancer). The proposed research is significant because it will begin to characterize this novel marker of risk, providing the foundation necessary for future studies exploring the relationship between BPE and breast cancer risk. PUBLIC HEALTH RELEVANCE: The proposed project has relevance to public health in that it seeks to characterize a new marker of breast cancer risk that has the potential to greatly improve the accuracy of breast cancer risk prediction in high-risk women undergoing breast MRI screening. This will help to guide decisions regarding subsequent follow-up, including preventative care. In the future, it may also prove to be useful as a non-invasive marker of response to chemoprevention measures and treatment, allowing for individualized adaptation of treatment regimens in real- time, and the development of truly personalized treatment protocols.